Heart failure (HF) is a chronic condition marked by impaired cardiac contractility leading to a systemic reduced organ blood perfusion, uncoupling the consumption and delivery of oxygen to the tissues, and eventually death. Hemodynamic and metabolic compensatory mechanisms are effective in a short-term, however may be deleterious in the long run. Pharmacological treatment of HF is based on partially counteracting the compensatory mechanisms, and improving myocardial contractility. In spite of best available pharmacologic therapy for heart failure which includes ACE-I/ARB, beta blocker, and aldosterone antagonists, morbidity and mortality remains high with approximately 30% of patients being hospitalized for heart failure within 3 months and a 50% survival from diagnosis (enter reference and update statistics based on AHA/ACC HF guidelines).
Compensatory elevated resting heart rate is considered a modifiable risk factor for patients with HF. Beta-blockers have been successful in reducing heart rate, among other actions, and improving morbidity and mortality of HF. However, a significant proportion of patients cannot tolerate the negative inotropic or lusitropic effects of beta-blockers and maintain elevated heart rates even under maximally tolerated dose of these agents. Ivabradine is a specific inhibitor of the If current in the sinoatrial node resulting in heart rate reduction that can result in an associated increase in the diastolic phase of the cardiac cycle and coronary artery filling without a change in myocardial contractility or relaxation. The efficacy and safety of ivabradine in reducing morbidity and mortality in HF was proven as an add-on therapy for patients under maximum tolerated background therapy and persistent elevated resting heart rate (above 70-75 bpm). However, symptomatic bradycardia may result from ivabradine use when the heart rate reduction exceeds the ability of compensatory physiologic mechanisms to maintain sufficient blood pressure.
Myocardial contractility is another target for HF therapies. Cardiac myosin activators like omecamtiv mecarbil are a new mechanistic class designed specifically to improve myocardial contractility. The mechanism of action of myosin activators increases the number of active myosin-actin interactions, resulting in an increase in the systolic ejection time, but not in the velocity of contraction, promoting an increase in stroke volume without significant increase in oxygen consumption. The availability of an oral formulation for chronic use, absence of arrhythmogenic effects, and no increase in myocardium oxygen consumption make omecamtiv mecarbil a promising therapeutic option for HF. An increase in systolic ejection time without a concomitant increase in diastolic time could reduce the time available for coronary artery filling.
Thus, HF remains a high unmet need condition which will benefit from development of additional therapeutic options that improve cardiac contractility while preserving coronary artery flow in diastole. Combination use of ivabradine and omecamtiv mecarbil provides an opportunity for the additive benefits of heart rate reduction and improved myocardial contractility in heart failure as derived from the individual therapies respectively. Additionally, there is an opportunity for mutual risk mitigation as symptomatic bradycardia that may result from ivabradine could be offset by improvements in myocardial contractility seen with omecamtiv mecarbil and reduction in diastolic coronary filling that may result from omecamtiv mecarbil could be offset by increased diastolic coronary filling that may result from ivabradine.